SARS-CoV-2的弗林蛋白酶切割位点在人类中的出现时间被限定在2019年末：对COVID-19起源的启示
Emergence of the SARS-CoV-2 furin cleavage site in humans is constrained to late 2019: implications for COVID-19 origins
AI总结：
该研究通过计算SARS-CoV-2的FCS与补偿突变D614G的等待时间，限定FCS出现于2019年末，为COVID-19起源提供了时间证据，排除了2019年末前人类隐秘传播FCS阳性病毒的可能。
AI中文摘要：
SARS-CoV-2的刺突蛋白中存在一个弗林蛋白酶切割位点（FCS）插入片段，其他 sarbecoviruses（沙贝病毒）中未发现该片段，它是该病毒在人类中传播的关键因素。FCS插入片段的起源尚不明确，关于其是自然产生还是人工插入一直存在争议。FCS会使刺突蛋白不稳定，因此在疫情早期，一种补偿突变D614G迅速出现并固定下来。利用一系列经实验确定的参数，等待时间计算可用于确定FCS出现与补偿突变D614G产生之间的时间间隔，该等待时间估计为37至65天。考虑到D614G的最早检测日期为2020年1月1日，FCS出现的最晚日期范围为2019年10月28日至11月25日。该时间线与从系统发育角度得出的SARS-CoV-2在2019年末出现的日期一致，表明FCS的出现与病毒的出现相对应。这种等待时间方法能够区分SARS-CoV-2出现的各种场景，特别是2019年末之前FCS阳性的祖先病毒在人类中隐秘传播的可能性较低，而FCS阳性的祖先病毒在蝙蝠中长时间传播则与缺乏补偿突变的情况不一致。
英文摘要：
SARS-CoV-2 possesses a furin cleavage site (FCS) insertion in its spike protein, that is not found in other sarbecoviruses, and is responsible for its transmissibility in humans. The origin of the FCS insertion is unclear, and has been a point of debate regarding whether it arose naturally, or represents an artificial insertion. The FCS is destabilizing to spike protein, and as a consequence a compensatory mutation, D614G, rapidly emerged during the early pandemic and swept to fixation. Using a range of empirically determined parameters, a waiting time calculation can be used to determine the time interval between the appearance of the FCS and generation of the compensating D614G mutation. The waiting time is estimated to range from 37 to 65 days. Given the earliest detection of D614G on 1 January 2020, the latest dates for the appearance of the FCS range from October 28 to November 25 2019. This timeline is consistent with dates generated from phylogenetic considerations for the emergence of SARS-CoV-2 in late 2019, indicating that FCS appearance and virus emergence correspond. The waiting time approach enables discrimination between various scenarios of SARS-CoV-2 emergence, in particular cryptic circulation of a FCS-containing progenitor in the human population prior to late 2019 is unlikely, while prolonged circulation of a FCS-containing progenitor in bats appears inconsistent with absence of the compensatory mutation.
